EP0190759A2 - 11-Beta phenyl gonanes, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

There were never 13-alkyl-11β-phenyl-gonanes of the general formula I <IMAGE> where A and B together for an oxygen atom, a CH2 group or a second bond between the carbon atoms 9 and 10, X for an oxygen atom or the hydroxyimino group N CH, R1 for a straight-chain or branched, saturated or unsaturated hydrocarbon radical with up to (8) carbon atoms, which the grouping? with X in the meaning given above, R2 for a or β-methyl or ethyl radical, R9, R10 and R11 and R12 each for a hydrogen atom, a hydroxyl, alkyl, alkoxy or acyloxy group each having 1 are up to 4 carbon atoms or a halogen atom and R3 and R4 have different meanings. The new 11β-phenyl gonans have anti-rod and anti-glucocorticoid effects.

Description

The invention relates to new 11β-phenyl gonans, processes for their preparation and pharmaceutical preparations containing these compounds according to the patent claims.

IIß-phenyl steroids are already known. For example, 11β-aryl-17α-propynyl and -ethynyl-4,9 (10) -estradienes are described in European Patent Application 82400025.1 (Publication No. 0 057 115) and U.S. Patent 4,386,085, 11β-Phenyl-17α- ( 3-hydroxypropyl) 4,9 (10) -estradienes in European patent application 84101721.3 (publication no. 0 116 974), 11β-phenyl-17α- (3-hydroxypropyl-1-enyl) -4.9 (10) -estradienes in European patent application 84730147.0 (publication no. 0 147 361) and 17β-hydroxy-17α- (3-hydroxypropyl) or 17α-Hydroxy-17β- (3-hydroxypropyl) -13α-methyl-4,9-gonane in European patent application 84730Q62.1 (publication no. 0 129 499). These compounds have a strong affinity for the gestagen receptor without having self-gestagen activity. They are competitive antagonists of progesterone (anti-progestogens) and are suitable for triggering abortions because they displace the progesterone required for maintaining pregnancy from the receptor. They are therefore valuable and interesting with regard to their use in post-co-fertility control. They can also be used to combat hormonal irregularities., For triggering menstruation and for inducing labor.

The compounds listed in European patent applications 84101721.3 and 84730147.0 have antimineralcorticoid effects in addition to their antigestagenic properties.

The first-mentioned 11β-aryl-17α-propynyl and -ethynyl-4,9 (10) -estradienes, on the other hand, have an antiglucocorticoid activity and can therefore also be used as drugs Therapy of corticoid-induced disorders (glaucoma) and to combat side effects that occur during long-term treatment with glucocorticoids (Cushing's syndrome). They therefore also make it possible to combat the disorders attributable to supersecretion of the glucocorticoids, especially obesity, arteriosclerosis, osteoporosis, diabetes and insomnia.

To date, however, it has not been possible to achieve a desired degree of dissociation between antigestagenic and antiglucocorticoid effects in these compounds. (G. Teutsch in "Adrenal Steroid Antagonism, Walter de Gruyter Berlin-New York, 1984, p. 43).

It has now been found that the new compounds of the general formula I surprisingly not only show very good antigestagenic and antiglucocorticoid effects, but that a separation of the two effects can also be observed in them.

The abortive effect was determined to identify the antigestagenic effect.

The experiments were carried out on female rats weighing approx. 200 g. After mating, the onset of pregnancy was confirmed by detecting sperm in vaginal smears. The day of the sperm detection is considered day 1 of pregnancy (= d1 p.c.).

The animals were treated with the substance to be tested or the solvent after the blastocysts were nidated from d5 pc to d7 pc. On d9 pc, the animals were sacrificed and the uteri were examined for implants and absorption sites. From Photos were taken of all the uteri. The absence of implants was considered an abortion.

The test substances were dissolved in a benzyl benzoate-castor oil mixture (ratio 1 + 9). The vehicle volume per single dose was _. 0.2 ml. The treatment was subcutaneous (s. _C. ).

Aus der Tabelle 1 ist zu entnehmen, daß nur die erfindungsgemäßen Verbindungen bei einer Dosis von 0,3 (A) bzw. 0,1 mg (B,C) abortiv voll wirksam sind, das heißt, sie sind um den Faktor 3 - 30 wirksamer als die Verbindungen des Standes der Technik.The superiority of the compounds according to the invention should be compared by comparing the biological properties of the compounds 11β- (4-acetylphenyl) -17β-hydroxy-17α- (1-propinyl) -4,9-estradien-3-one (A), 17β-hydroxy -17α- (3-hydroxy-1 (Z) -propenyl) -11β- (4-propynylphenyl) -4,9-estradien-3-one (B) and 11β- (4-acetylphenyl) -17β-hydroxy -17α- (3-hydroxy-1 (Z) -propenyl) -4,9-estradien-3-one (C), the 11β- (4-dimethylaminophenyl) -17β-hydroxy-17α- (propyne described in EP 82400025.1 -1-yl) -4,9 (10) -estradien-3-one RU 38486 (D), the 11β- (4-dimethylaminophenyl) -17β-hydroxy-17α- (3-hydroxypropyl) -4 described in EP 84101721.3 , 9 (10) -estradien-3-one (E), the 11β- (4-dimethylaminophenyl) -17β-hydroxy-17α- (3-hydroxyprop-1 (Z) -enyl) -4.9 described in EP 84730147.0 (10) -estradien-3-one (F) and the 11β- (4-dimethylaminophenyl) -17β-hydroxy-17α- (3-hydroxypropyl) -13α-methyl-4,9-gonadien-3- described in EP 84730062.1 on (G) and 11β- (4-dimethylaminophenyl) -17α-hydroxy-17β- (3-hydroxypropyl) -13α-methyl-4,9 -gonadien-3-one (H) are shown:

It can be seen from Table 1 that only the compounds according to the invention are fully effective at a dose of 0.3 (A) or 0.1 mg (B, C), that is to say they are by a factor of 3-30 more effective than the prior art compounds.

To characterize the antiglucocorticoid effect, the influence of the substances according to the invention on the tyrosine aminotransferase was determined. The test system is based on a measurement of the activity of the liver enzyme tyrosine aminotransferase (TAT) in cultures of RHC (Rat Hepatoma Cells) cells. The enzyme catalyzes the first step in the metabolism of tyrosine and is inducible in the liver as well as in hepatoma cells by glucocorticoids. The activity is easily measurable in crude extracts (Granner and Tomkins, (1970) Meth. Enzymol. 15, 633). The enzyme converts the amino group from tyrosine to 2-oxoglutaric acid. This creates glutamic acid and p-hydroxyphenyl pyruvate. In alkaline solution, the more stable p-hydroxybenzaldehyde is formed from p-hydroxyphenyl pyruvate, the absorption of which is measured at 331 nm. The TAT activity in RHC cells shows a dose-dependent induction with cortisol (max. Act. At 10 ^-6 M) or dexanethasone (max. Act. At 10 ^-7 M). The activity can be stimulated by a factor of 4-6 above the basal value. Simultaneous treatment with corticoid and antiglucocorticoid leads to a decrease in TAT activity.

In this test, the compound A according to the invention shows 30%, the compounds B and C according to the invention less than 1%, of the activity of R _U 38.486 (D), a substance which is to be regarded as the standard (7th International Congress of Endocrinology July 1- 7, 1984, Quebec City, Canada; Excerpta Medica, Amsterdam-Oxford-Princeton).

Since the compound (A) is 10 times more active and the compounds (B) and (C) 30 times more antigestagen than (D), this results in a clear dissociation of the antiglucocorticoids and antigestagen properties.

A further example according to the invention is 11β- / 4- (ariti-hydroxy- "iminomethyl) -phenyl] -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one-anti-oxime (J This compound shows an antiglucocorticoid effect comparable to (D), but is at least 10 times weaker than (D) in the antigestagen test.

In the gestagen receptor binding test, the affinity of the compounds according to the invention for the gestagen receptor is examined. The displacement of the agonist by the antagonist is measured.

One uses cytosol from rabbit uterine homogenate, which contains the receptor molecule - a protein. This binds progesterone with high affinity and low capacity. If these receptors are loaded with ³ H-progesterone in the presence of the unlabeled substance to be tested, it depends on the concentration and on the binding affinity of the compound to be examined how strongly ³ H-progesterone is displaced by the receptor. After separating the receptor-bound progesterone from the unbound one, the binding can be determined in percent and this value plotted against the logarithm of the molar concentration of the test substance. Characteristic dose-dependent displacement curves are obtained and the concentration of the test substance which is required to completely displace the reference substance from the receptor can now be determined. The competition factor K as a measure of the binding strength is defined as the ratio of the concentration of the test substance to the concentration of the reference substance (Progesterone), in which both compounds show an equal displacement of ³ H-progesterone from the progesterone-receptor complex, so that a low K value indicates high binding strength (high affinity).

The table shows that the compounds A, B, C according to the invention mentioned for example 11β- (4-formylphenyl) -17β-hydroxy-17α (1-propynyl) -4,9-estradien-3-one (I), 17β-hydroxy -17α- (1-propynyl) -11β- (4-propionylphenyl) -4,9-estradien-3-one (K), 11β- (4-acetylphenyl) -17β-hydroxy-9α, 10α-methylene-17α- (1-propynyl) -4-estren-3-one (L) and 3- [11β- (4-acetylphenyl) -17β-hydroxy-3-oxo-4,9-estradien-17α-yl] propionic acid lactone (M ) are up to 4 times more effective in the gestagen receptor binding test than the compound (D) which is to be regarded as a standard.

The invention also relates to pharmaceutical preparations which contain compounds of the general formula I.

The pharmacologically active compounds of the general formula I according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous or parenteral administration by methods known per se in galenics.

The dosage of the compounds according to the invention in humans is about 1 to 1000 mg, preferably 5 to 200 mg, per day.

Gruppe direkt an den Phenylring gebunden ist, bevorzugt, d.h. also die Formyl-, Acetyl-, Propionyl- und Butyrylgruppe bzw. deren Hydroxyimino-Derivate. Im Falle der ungesättigten Kohlerwasserstoffreste sind α,β-ungesättigte

Gruppierungen, bei denen die C-Atome 1 und 2 der Kette die Doppelbindung tragen, bevorzugt.The hydrocarbon groups contained in R _{1 of} the general formula I should have up to 8, preferably up to 4, carbon atoms. In the case of saturated alkyl radicals are substitutions in which the

Group is bonded directly to the phenyl ring, preferably, ie the formyl, acetyl, propionyl and butyryl group or their hydroxyimino derivatives. In the case of unsaturated hydrocarbon residues, α, β-unsaturated ones

Groups in which the C atoms 1 and 2 of the chain carry the double bond are preferred.

The alkyl, acyl and alkoxy groups contained in R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ , R ₁₁ and R12 or R _{8 of} the general formula 1 should each contain 1 to 4 or Contain 1 to 10 carbon atoms, the methyl, ethyl, propyl, formyl, acetyl, propionyl, butyryl, methoxy and ethoxy group being preferred.

Of the alkenyl radicals, the propenyl group, which may be in the E or Z configuration, is preferred, ie if R _{4 is} -CH = CH- (CH ₂ ) _k -CH ₂ -R ₆ , then k should preferably be zero . If R ₉ , R ₁₀ , R ₁₁ and R _{12 represent} halogen, chlorine is preferred. In the case of the substituents R ₉ , R ₁₀ , R ₁₁ and R ₁₂ , mono substitution is preferred, ie three of these substituents then represent hydrogen atoms.

The new 13-alkyl-11β-phenylgonanes of the general formula I are prepared according to the invention by the process according to claim 36.

Starting from the compounds of the general formula II, treatment with acid or an acidic ion exchanger is carried out for elimination of water with formation of the 4 (5) double bond and for the simultaneous removal of protective groups present. The acidic treatment is carried out in a manner known per se by dissolving the compound of the formula II, which contains at least two protective groups, in a water-miscible solvent, such as aqueous methanol, ethanol or acetone, and catalytic amounts of mineral or sulfonic acid on the solution , such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid, or an organic acid, such as acetic acid, can act until water is split off and protective groups are removed. The reaction, which takes place at temperatures from 0 to 100 ° C, can also be carried out with an acidic ion exchanger. The course of the reaction can be followed using analytical methods, for example samples taken by thin-layer chromatography.

The in the general formula II of K, K ₁ , R ' ₃ . and R ' ₄ . Protected groups included in the acidic environment are easily removable groups, such as, for example, the ethylenedioxyketal, ethylenedithioketal, 2,2-dimethyltrimethylenedioxyketal, hydroxyimino, methoxyimino, tetrahydropyranyl, methoxymethyl or ethoxymethyl group.

If a compound of the general formula II is used, the K1 of which contains a protected hydroxyl group, then this is subsequently treated with one of the oxidizing agents customary for the oxidation of allylic hydroxyl groups, such as, for example, Chromic acid, pyridine, pyridinium dichromate, pyridinium chlorochromate, manganese dioxide, silver carbonate on Celite, converted into the oxo function. The reaction with manganese dioxide carried out at temperatures between -20 ° C. and +40 ° C. is preferred.

The introduction of hydroxyl groups into positions 6, 7, 15 and 16 of the steoid structure of the general formula II with R ₉ , R ₁₀ , R ₁₁ and R ₁₂ each meaning one hydrogen atom is carried out with the aid of microorganisms.

For example, 6α-hydroxylation takes place if microorganisms of the species Nigrospora shaerica (CBS 98469) are used for the fermentation. With Neurospora crassa (ATCC 9278) 7α-, with Streptomyces platensis (NRRL 2364) 15ß- and with Streptomyces toyocaensis (DSM 40030) 16α-hydroxylation.

The fermentations are carried out under the conditions which are usually used in the microbiological hydroxylation of steroids with microorganisms. It shall first be in generally customary preliminary tests, the best fermentation conditions, such as selecting the most favorable nutrient medium, the suitable substrate solvent or suspension means, the substrate concentration, the technical conditions such as temperature, aeration, pH and the optimum times for Germina _t ion, substrate addition and substrate contact on the enzyme of the microorganism is determined analytically, in particular by thin layer chromatography.

It is expedient to use the substrate in a concentration of approximately 100 to 5000 mg per liter of nutrient medium. The pH is preferably adjusted to a range from 5 to 7.5. The cultivation temperature is in the range from 20 to 40 ° C, preferably from 25 to 35 ° C. For ventilation, 0.5 to 5 liters of air per minute per liter of culture broth are preferably added. The conversion of the substrate is expediently followed by thin-layer chromatography analysis. The fermentation time is about 30 to 130 hours.

A reversal of the configuration of these secondary alcohols is in itself known methods, preferably after the Mitsunobu reaction with azodicarboxylic acid ester / triphenylphosphine (Synthesis 1981.1, Chem. Commun. 1981, 840).

The halogen substituents are introduced into the C-6, C-7, C-15 or C-16 position of the steroid structure by methods known from the literature by nucleophilic substitution of the corresponding hydroxyl groups with inversion, preferably with triphenylphosphine and a halogen source such as CCl ₄ or CBr ₄ (Chem. Ind. 1966, 900, Ca.n. J. Chem. 1982, 210, JCS Perkin I 1982, 681, Synthesis 1983, 139) or in the case of the fluoride substituent with (diethylamino) sulfur trifluoride (U.S. Patent 3,914,265 J. Org. Chem. 1983, 393).

If the introduction of a C-6, C-7, C-15 or C-16 alkyl substituent is desired, the corresponding hydroxylated starting materials are also used. After conversion to a suitable escape group such as, for example, mesylate, tosylate, iodide, bromide, but preferably tosylate, the hydroxyl group is converted by reaction with lithium dialkyl cuprates or organocuprates of the formula alkyl ₂ Cu (CN) Li ₂ (J. Am.Chem.Soc. 103 , 7672 (1981)).

The compounds of general formula I with X in the meaning of an oxygen atom which are obtained in this way can, if desired, be converted into the oximes by reaction with hydroxylamine hydrochloride in the presence of tertiary amines at temperatures between -20 and +40.degree. C. ~ OH, where the hydroxy group can be syn- or anti-resistant) are transferred. Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] nonen-5 (DBN) and 1,5-diazabicyclo [5.4.0] undecen-5 (DBU) , with pyridine being preferred.

If esterification of compounds of the general formula I whose R ₃ , R ₄ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ contains a hydroxy group is desired, this acylation is carried out in a manner known per se, for example by reaction with the acid anhydride in pyridine at room temperature.

worin R₂ β-ständig ist.The preparation of the starting compounds of the general formula II starts, as described, for example, in European patent applications 84101721.3 and 82400025.1, from the epoxide of the general formula III

where R _{2 is} β-permanent.

The 11β-phenyl radical is introduced to form the Δ ^9,10 -5α-hydroxy structural element either by Cu (I) -catalyzed Grignard reaction with the corresponding arylmagnesium halides (Tetrahedron Letters 1979, 2051) or by reaction with mixed organocuprates of the type R ₂ Cu (CN) Li ₂ (J. Amer. Chem. Soc. 103 (1981) 7672).

mit ultraviolettem Licht.Access to the 13α-methyl or 13α-ethyl series (R ₂ is α-permanent) is achieved - as described, for example, in European patent application 84730062.1 - by irradiation of intermediates of the general formula IV

with ultraviolet light.

The introduction of a 9, 10-epoxy or methylene group (A and B together represent an oxygen atom or a CH ₂ group) takes place at the step of Δ ^9.10 -5α, 17-dihydroxy-11β-phenyl Intermediate product by methods known per se by reaction with, for example, hydrogen peroxide, organic peracids, such as, for example, m-chloroperbenzoic acid or perphthalic acid, tert. Butyl hydroperoxide or with, for example, methylene iodide or methylene bromide / zinc (Simmons-Smith).

The substituents R ₃ and R ₄ are introduced by the customary methods of building up the C side chain by nucleophilic addition to the 17-ketone and subsequent reactions ("Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society, London, Vol. 1-12 ). While the nucleophilic addition to the 17-ketone of the 13β-alkyl series only gives adducts with the hydroxyl group in the β- and the incoming group in the α-position to the five-membered ring, the addition to the corresponding 13 epi-17-ketone generally proceeds to form both possible isomeric forms at C-17, which are, however, easily separable by chromatography or fractional crystallization. In many cases, both isomers are pharmacological effective, although there may be differences in effectiveness.

The nucleophilic addition of HC≡CX, in which X is hydrogen, alkyl having 1 to 4 carbon atoms or halogen, takes place with the aid of a compound of the general formula MC≡CX, in which X has the meaning given above and represents my alkali metal.

The organometallic compound can also be formed in situ and reacted with the 17-ketone. For example, acetylene and an alkali metal, in particular potassium, sodium or lithium, can be allowed to act on the 17-ketone in a suitable solvent in the presence of an alcohol or in the presence of ammonia. The alkali metal can also act in the form of, for example, methyl or butyllithium. Dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene are particularly suitable as solvents.

To prepare the 17-chloroethynyl compound, the organometallic chloroethynyl compound is formed in situ from 1,2-dichloroethylene and an ethereal alkali metal solution, such as, for example, methyl or butyllithium solution, and reacted with the 17-ketone in solvents, such as tetrahydrofuran or diethyl ether.

17-bromoethynyl compounds can also be prepared by bromination of the corresponding ethynyl starting material (Angw. Chem. 96, 720 (1984)).

The 17-ethynyl-17-hydroxy compounds can be hydrated in alcoholic solution under mercury salt catalysis to give the 17-acetyl-17-hydroxy compounds (Chem. Ber. 111 (1973) 3086-3093).

3-Hydroxypropine, propene or propane is introduced in the 17-position by reacting the 17-ketone with metalated derivatives of propargyl alcohol, for example with 1-lithium-3-tetrahydropyran-2'-yloxypropin-1, to the 17- (3-hydroxy-1-propynyl) -17-hydroxy compounds, which can subsequently be hydrogenated to the 17- (3-hydroxypropyl or 3-hydroxypropenyl) -17-hydroxy compounds. The hydrogenation must be carried out under conditions which only ensure attack on the C-C triple bond without saturating the tetrasubstituted 9 (10) double bond which may be present. This can be achieved, for example, by hydrogenation at room temperature and normal pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with the addition of noble metal catalysts such as platinum or palladium.

The homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane groups are introduced in a corresponding manner with homologues of propargyl alcohol.

The compound with the Z-configured double bond in the hydroxypropenyl group is formed by hydrogenating the acetylenic triple bond with a deactivated noble metal catalyst (J. Fried, JA Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, page 134, and HO House: Modern Synthetic Reactions 1972, page 19). Examples of deactivated noble metal catalysts are 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead (II) acetate. The hydrogenation is stopped after the absorption of one equivalent of hydrogen.

The compound with the E-configured double bond in the hydroxypropenyl group is formed by reducing the acetylenic triple bond in a manner known per se. The literature describes a whole series of methods for converting alkynes into trans-olefins, for example the reduction with sodium in liquid Ammonia (J. Am. Chem. Soc. 63 (1941) 216), with sodium amide in liquid ammonia (J. Chem. Soc. 1955, 3558), with lithium in low molecular weight amines (J. Am. Chem. Soc. 77 ( 1955) 3378), with boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1971) 6560), with diisobutylaluminum hydride and methyl lithium (J. Am. Chem. Soc. 89 (1967) 5085) and especially with lithium aluminum hydride / alcoholate (J. Am. Chem. Soc. 89 (1967) 4245). Another possibility is the reduction of the triple bond with chromium (II) sulfate in the presence of water or dimethylformamide in a weakly acidic medium (J. Am. Chem. Soc. 86 (1964) 4358) and generally the reduction by the action of transition metal compounds with alternation the oxidation level.

so wird die 17-(3-Hydroxypropyl)-Verbindung in an sich bekannter Weise oxydiert, zum Beispiel mit Jones' Reagenz, Braunstein, Pyridiniumdichromat, Pyridiniumchlorochromat, Chromsäure-Pyridin oder dem Fetizon-Reagenz Silbercarbonat/ Celite (Compt. rend. 267 (1968) 900).If end products of the formula I are desired with R ₃ / R ₄ in the meaning of

the 17- (3-hydroxypropyl) compound is oxidized in a manner known per se, for example using Jones' reagent, manganese dioxide, pyridinium dichromate, pyridinium chlorochromate, Chromic acid pyridine or the Fetizon reagent silver carbonate / Celite (Compt. Rend. 267 (1968) 900).

wird das 17-Keton mit Tosylmethylisocyanid in die 17-Nitrilverbindung überführt, aus der 17-Nitrilverbindung wird mit Methyllithium oder Methylmagnesiumbromid die 17-Acetylverbindung erhalten, welche nach Enolisierung mit K-tert.-Butylat in Tetrahydrofuran und Umsetzung mit Methyljodid die gewünschte Gruppierung in 17-Stellung liefert.To introduce grouping

the 17-ketone is converted into the 17-nitrile compound with tosylmethyl isocyanide, the 17-acetyl compound is obtained from the 17-nitrile compound with methyl lithium or methyl magnesium bromide, which, after enolization with K-tert-butoxide in tetrahydrofuran and reaction with methyl iodide, gives the desired grouping 17 position delivers.

The 17-cyanomethyl side chain is built up in a manner known per se from the 17-ketone, for example via the 17-spiroepoxide and cleavage of the spiroepoxide with HCN according to Z. Chem. 18 (1978) 259-260.

The 17-hydroxyacetyl side chain is also introduced by methods known per se, for example by the method described in J. Org. Chem. 47 (1932), 2993-2995.

Free hydroxyl groups in the 6-, 7-, 15-, 16- or 17-position can be esterified or etherified in a manner known per se.

The strains Neurospora crassa (ATCC 9278), Nigrospora shaerica (CBS 98469), Streptomyces platensis (NRRL 2364) and Streptomyces toyocaensis have been deposited with the German Collection of Microorganisms under the numbers DSM 894, DSM 3392, DSM 40041 and DSM 40030.

Example 1 17α-ethynyl-11β- (4-formylphenyl) -17β-hydroxy-4,9-estradien-3-one

A solution of 9.0 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -17α-ethynyl -9-estrene-5α, 17β-diol in 90 ml of 70% aqueous acetic acid is stirred at 50 ° C for 30 minutes. After cooling, the mixture is poured into ice water, neutralized by adding aqueous ammonia solution and extracted with dichloromethane. Crystallization of the crude product from ethyl acetate / diisopropyl ether gives 5.3 g of 17α-ethynyl-11β- (4-formylphenyl) -17β-hydroxy-4,9-estradien-3-one with a melting point of 197-198 ° C.

• a) Eine Lösung von 25 g 4-Brombenzaldehyd in 250 ml Dichlormethan wird nach sukzessiver Zugabe von ₃₇,5 g 2,2-Dimethyl-propan-1,3-diol, ₁8,75 ml Orthoameisensauretrimethylester und 20 mg p-Toluolsulfonsäure 24 Stunden bei Raumtemperatur gerührt. Zur Aufarbeitung gießt man in gesättigte, wäßrige NaHCO₃-Lösung und extrahiert mit Diethylether. Nach Kristallisation des Rohprodukts aus Hexan erhält man 37,1 g 4-(5,5-Dimethyl-1,3-dioxan-2-yl)-brombenzol vom Schmelzpunkt 62 - 64 °C.
• b) Zu einer Suspension von 4,5 g Magnesiumspänen in 120 ml absoluten (abs.) Tetrahydrofuran (THF) gibt man bei 25 C zunächst 0,05 ml Iodmethan und anschließend eine Lösung von 54 g 4-(5,5-Dimethyl-1,3-dioxan-2-yl)-brombenzol in 270 ml abs. THF so hinzu, daß die Innentemperatur 45 °C nicht übersteigt. Nach vollständiger Auflösung des Magnesiums kühlt man auf +5 °C und gibt portionsweise 1,07 g CuCl zur Reaktionslösung. Man rührt 15 Minuten nach und gibt anschließend bei +5 °C eine Lösung von 25,4 g 3,3-(2,2-Dimethyl-trimethylendioxy)-5α,10α-epoxy-9(11)-estren-17ß-ol in 250 ml abs. THF tropfenweise hinzu. Nach erfolgter Zugabe rührt man weitere 2 Stunden bei Raumtemperatur, gießt die Reaktionslösung dann in ein Gemisch aus Eiswasser/wäßriger Ammoniaklösung und extrahiert mit Ethylacetat. Das so erhaltene ölige Rohprodukt wird mit Hexan/Ethylacetat an Aluminiumoxid (Merck, Stufe III, neutral) chromatographiert. Nach Kristallisation der Hauptfraktion aus Ethylacetat/ Diisopropylether erhält man 33,8 g 3,3-(2,2-Dimethyl- trimethylendioxy)-11β-[4-(5,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-9-estren-5α,17β-diol vom Schmelzpunkt 218 - 220 °C.
• 
  c) Eine Suspension aus 12,7 g des unter b) erhaltenen Produkts, 74 ml Cyclohexanon, 7,1 g Aluminiumisopropylat und 494 ml Toluol wird 4 Stunden unter Rückfluß erhitzt, wobei man ca. ein Drittel der Lösungsmittelmenge abdestillieren läßt. Nach dem Abkühlen gießt man in Eiswasser, filtriert die entstandene Emulsion über Celite, wäscht den Filterrückstand gründlich mit Ethylacetat, trennt die organische Phase des Filtrats ab, trocknet diese über Na₂SO₄ und engt ein. Nach Chromatographie über Al₂O₃, neutral, Stufe III, mit Hexan/Ethylacetat und Kristallisation der Hauptfraktion aus Hexan/Ethanol erhält man 9,6 g 3,3-(3,2-Dimethyl- trimethylendioxy)-11β-[4-(5,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-5α-hydroxy-9-estren-17-on vom Schmelzpunkt 209 - 211 °C.
  
• d) Abs. THF (495 ml) wird 30 Minuten bei 0 °C mit Acetylen gesättigt. Anschließend tropft man 100 ml einer 15 %igen Lösung von n-Butyllithium in Hexan hinzu und danach eine Lösung von 8,75 g des unter c) erhaltenen Ketons in 135 ml THF. Man rührt 3,5 Stunden bei Raumtemperatur nach, gießt dann in ca. 2 1 Eiswasser und extrahiert mit Ethylacetat. Das so erhaltene ölige Rohprodukt (9,0 g) wird ohne weitere Reinigung in die Endstufe eingesetzt.

The raw material is manufactured in the following way:.

• a) A solution of 25 g of 4-bromobenzaldehyde in 250 ml of dichloromethane is added after successive addition of _37.5 g of 2,2-dimethyl-propane-1,3-diol, ₁ 8.75 ml of trimethyl orthoformate and 20 mg of p-toluenesulfonic acid 24 Stirred for hours at room temperature. For working up, the mixture is poured into saturated, aqueous NaHCO ₃ solution and extracted with diethyl ether. After crystallization of the crude product from hexane, 37.1 g of 4- (5,5-dimethyl-1,3-dioxan-2-yl) bromobenzene with a melting point of 62-64 ° C. are obtained.
• b) 0.05 ml of iodomethane and then a solution of 54 g of 4- (5,5-dimethyl-) are first added to a suspension of 4.5 g of magnesium shavings in 120 ml of absolute (absolute) tetrahydrofuran (THF) at 25 ° C. 1,3-dioxan-2-yl) bromobenzene in 270 ml abs. THF like that added that the internal temperature does not exceed 45 ° C. After the magnesium has completely dissolved, the mixture is cooled to +5 ° C. and 1.07 g of CuCl are added in portions to the reaction solution. The mixture is stirred for a further 15 minutes and then a solution of 25.4 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -5α, 10α-epoxy-9 (11) -estren-17ß-ol is added at +5 ° C. in 250 ml abs. Add THF dropwise. After the addition is complete, the mixture is stirred for a further 2 hours at room temperature, then the reaction solution is poured into a mixture of ice water / aqueous ammonia solution and extracted with ethyl acetate. The oily crude product thus obtained is chromatographed on aluminum oxide (Merck, stage III, neutral) using hexane / ethyl acetate. After crystallization of the main fraction from ethyl acetate / diisopropyl ether, 33.8 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) are obtained. -phenyl] -9-estrene-5α, 17β-diol with melting point 218-220 ° C.
• 
  c) A suspension of 12.7 g of the product obtained under b), 74 ml of cyclohexanone, 7.1 g of aluminum isopropylate and 494 ml of toluene is heated under reflux for 4 hours, allowing about a third of the amount of solvent to be distilled off. After cooling, the mixture is poured into ice water, the resulting emulsion is filtered through Celite, the filter residue is washed thoroughly with ethyl acetate, the organic phase of the filtrate is separated off, dried over Na ₂ SO ₄ and concentrated. After chromatography over Al ₂ O ₃ , neutral, stage III, with hexane / ethyl acetate and crystallization of the main fraction from hexane / ethanol, 9.6 g of 3,3- (3,2-dimethyl-trimethylene-dioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -5α-hydroxy-9-estren-17-one, melting point 209-211 ° C.
  
• d) Abs. THF (495 ml) is saturated with acetylene at 0 ° C for 30 minutes. 100 ml of a 15% strength solution of n-butyllithium in hexane are then added dropwise, followed by a solution of 8.75 g of the ketone obtained in c) in 135 ml of THF. The mixture is stirred for 3.5 hours at room temperature, then poured into about 2 l of ice water and extracted with ethyl acetate. The oily crude product (9.0 g) thus obtained is used in the final stage without further purification.

Example 2 11β- (4-formylphenyl) -17ß-hydroxcy-17α- (1-propynyl) -4,9-estradien-3-one

20.1 g 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -17α- (1-propyl ) -9- estrene-5α, 17β-diol are stirred in 83 ml of 70% aqueous acetic acid for 30 minutes at 60 ° C. and worked up under the conditions of Example 1. After crystallization of the crude product from methylene chloride / diisopropyl ether, 10.6 g of the title compound of melting point 207-203 ° C. are obtained.

• Abs. THF (1040 ml) wird durch 30minütiges Einleiten bei 0 °C mit Methylacetylen gesättigt. Anschließend tropft man bei O bis +5 °C 84,4 ml einer 15 %igen Lösung von n-Eutyllithium hinzu, rührt nach Zugabe 15 Minuten und gibt dann eine Lösung von 19,4 g 3,3-(2,2-Dimethyl-trimethylendioxy)-11ß-[4-(5,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-5α-hydroxy-9-estren-17-on (s. Beispiel 1 c)) tropfenweise hinzu. Man rührt weitere 60 Minuten bei Raumtemperatur, gießt in Eiswasser und extrahiert mit Ethylacetat. Das Rohprodukt. (20,1 g) wird ohne weitere Reinigung in die Endstufe eingesetzt.

The raw material is manufactured in the following way:

• Abs. THF (1040 ml) is saturated with methyl acetylene by introducing it at 0 ° C. for 30 minutes. 84.4 ml of a 15% solution of n-eutyllithium are then added dropwise at 0 to + 5 ° C., the mixture is stirred for 15 minutes after addition and then a solution of 19.4 g of 3,3- (2,2-dimethyl -trimethylenedioxy) -11ß- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -5α-hydroxy-9-estren-17-one (see Example 1 c)) dropwise added. You stir another 60 minutes at room temperature, poured into ice water and extracted with ethyl acetate. The raw product. (20.1 g) is used in the final stage without further purification.

Example 3 11β- (4-formylphenyl) -17α-hydroxy-13α-methyl-17β- (1-propynyl) -4,9-gonadien-3-one

Under the conditions of Example 1, 1.1 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl is used ] -13α-methyl-17β- (1-propynyl) -9- gonen-5α, 17α-diol with 15 ml of 70% acetic acid at 60 ° C. After chromatography of the crude product on silica gel with hexane / ethyl acetate, 530 mg of the title compound are obtained amorphously.

• a) Eine Lösung von 4,0 g des unter 1 c) erhaltenen Ketons in 600 ml Dioxan wird in einer Quarzglas-Tauchapparatur 35 Minuten bei 25 °C mit einer Hg-Hochdrucklampe (Philips HPK 125) bestrahlt. Das Lösungsmittel wird anschließend im Wasserstrahlvakuum entfernt und der ölige Rückstand an Al₂O₃ (Merck, neutral, Stufe III) mit Hexan/Ethylacetat chromatographiert. Kristallisation der Hauptfraktion aus Diisopropylether ergibt 2,05 g 3,3-(2,2-Dimethyl-trimethylendioxy)-11β-[4-(3,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-5α-hydroxy-13α-methyl-9-gonen-17-on vom Schmelzpunkt 135 - 187 °C.
  
• b) Unter den Bedingungen des Beispiels 2 a) werden 1,9 g des unter a) erhaltenen Ketons mit Methylacetylen umgesetzt. Nach Chromatographie des Rohprodukts an Al₂O₃ mit Hexan/Ethylacetat und Kristallisation der Hauptfraktion aus CH₂Cl₂/Ethylacet erhalt man 1,22 g 3,3-(2,2-Dimethyl-trimethylendioxy)-11β-[4-(5,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-13α-methyl-17β-(1-propinyl)-9-gonen-5α,17α-diol vom Schmelzpunkt ₂4₀ - ₂4₃ °C.
  

The raw material is manufactured in the following way:

• a) A solution of 4.0 g of the ketone obtained in 1 c) in 600 ml of dioxane is irradiated in a quartz glass immersion apparatus for 35 minutes at 25 ° C. with a high pressure mercury lamp (Philips HPK 125). The solvent is then removed in a water jet vacuum and the oily residue is chromatographed on Al ₂ O ₃ (Merck, neutral, stage III) using hexane / ethyl acetate. Crystallization of the main fraction from diisopropyl ether gives 2.05 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- (3,5-dimethyl-1,3-dioxan-2-yl) phenyl] - 5α-hydroxy-13α-methyl-9-gonen-17-one with a melting point of 135-187 ° C.
  
• b) Under the conditions of Example 2a), 1.9 g of the ketone obtained under a) are reacted with methyl acetylene. After chromatography of the crude product on Al ₂ O ₃ with hexane / ethyl acetate and crystallization of the main fraction from CH ₂ Cl ₂ / ethyl acetate, 1.22 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- ( 5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -13α-methyl-17β- (1-propynyl) -9-gonen-5α, 17α-diol with melting point ₂ 4 ₀ - ₂ 4 ₃ ° C.
  

Example 4 11β- (3-formylphenyl) -17β-hydroxy-17α- (1-propynyl) -4, 9-estradien-3-one

2.7 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [3- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -17α- (1-propynyl ) -9- estrene-5α-17β-diol are cleaved under the conditions of Example 1 with 30 ml of 70% acetic acid. After crystallization of the crude product thus obtained from dichloromethane / acetone, 1.15 g of the title compound of melting point 260-262 ° C. is obtained.

Die Herstellung des Ausgangsmaterials erfolgt auf folgendem Wege:

• a) Aus 31,7 ml 3-Brombenzaldehyd, 75 g 2,2-Dimethyl-propan-1,3-diol, 37,6 ml Orthoameisensäuretrimethylester und 50 mg p-Toluolsulfonsäure in 500 ml Dichlormethan erhält man unter den Bedingungen des Beispiels 1 a) nach Kristallisation aus Hexan 73,0 g 3-(5,5-Dimethyl-1,3-dioxan-2-yl)-methyl-brombenzol vom Schmelzpunkt 42 - 43 °C.
• b) Aus 15,0 g 3,3-(2,2-Dimethyl-trimethylendioxy)-5α,10α-epoxy-9(11)-estren-17ß-ol, 62,2 g des unter a) erhaltenen Ketals, 4,82 g Magnesium, 0,08 ml Iodmethan und 1,02 g CuCl in 420 ml THF erhält man unter den Bedingungen des Beispiels 1 b) nach Chromatographie über Al₂O₃ mit Hexan/Ethylacetat 19,6 g 3,3-(2,2-Dimethyl-trimethylen- dioxy)-11β-[3-(5,5-dimethyl-1,3-dioxan-2-yl)-]-9 estren-5α,17ß-diol als farbloses Öl.
• c) Oppenauer-Oxidation des unter b) erhaltenen Produkts (18,0 g), 10,3 g Aluminiumisopropylat, 112 ml Cyclohexanon, 560 ml Toluol unter den Bedingungen des Beispiels 1 c) ergibt nach Kristallisation des Rohprodukts aus Diisopropylether 13,8 g des 17-Ketons vom Schmelzpunkt 195 - 197 °C.
  
• d) Unter den Bedingungen des Beispiels 2 a) werden 2,5 g des unter c) erhaltenen Ketons mit dem Lithiumderivat des Methylacetylens umgesetzt. Das Rohprodukt (2,7 g) wird ohne weitere Reinigung in die Endstufe eingesetzt.

The raw material is manufactured in the following way:

• a) 31.7 ml of 3-bromobenzaldehyde, 75 g of 2,2-dimethyl-propane-1,3-diol, 37.6 ml of trimethyl orthoformate and 50 mg of p-toluenesulfonic acid in 500 ml of dichloromethane are obtained under the conditions of Example 1 a) after crystallization from hexane, 73.0 g of 3- (5,5-dimethyl-1,3-dioxan-2-yl) methyl bromobenzene with a melting point of 42-43 ° C.
• b) From 15.0 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -5α, 10α-epoxy-9 (11) -estren-17ß-ol, 62.2 g of the ketal obtained under a), 4 , 82 g magnesium, 0.08 ml iodomethane and 1.02 g CuCl in 420 ml THF are obtained under the conditions of Example 1 b) after chromatography over Al ₂ O ₃ with hexane / ethyl acetate 19.6 g 3.3- ( 2,2-Dimethyl-trimethylene-dioxy) -11β- [3- (5,5-dimethyl-1,3-dioxan-2-yl) -] - 9 estren-5α, 17ß-diol as a colorless oil.
• c) Oppenauer oxidation of the product obtained under b) (18.0 g), 10.3 g of aluminum isopropylate, 112 ml of cyclohexanone, 560 ml of toluene under the conditions of Example 1 c) gives, after crystallization of the crude product from diisopropyl ether, 13.8 g of the 17-ketone with a melting point of 195-197 ° C.
  
• d) Under the conditions of Example 2a), 2.5 g of the ketone obtained under c) are reacted with the lithium derivative of methyl acetylene. The crude product (2.7 g) is used in the final stage without further purification.

Example 5 11β- (3-formylphenyl) -17α-hydroxy-13α-methyl-17β- (1-propynyl) -4,9-gonadien-3-one

Die Herstellung des Ausgangsmaterials erfolgt auf folgendem Wege:

• a) Unter den Bedingungen des Beispiels 3 a) bestrahlt man eine Lösung von 3,5 g des unter Beispiel 4 c) erhaltenen . Ketons in 525 ml Dioxan. Durch Chromatographie des Rohprodukts an Al₂O₃ mit Hexan/Ethylacetat und Kristallisation der Hauptfraktion aus Diisopropylether erhält man 1,97 g 3,3-(2,2-Dimethyl-trimethylendioxy)-11ß-[3-(5,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-5α-hydroxy-13α-methyl-9-gonen-17-on vom Schmelzpunkt 209 - 211 °C.
  
• b) Durch Umsetzung des unter a) erhaltenen Produkts (1,8 g) mit Methylacetylen unter den Bedingungen des Beispiels 2 a) erhält man nach Chrocatographie und Kristallisation aus Ethylacetat/Diisopropylether 1,12 g 3,3-(2,2-Dimethyl- trimethylendioxy)-11ß-[3-(3,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-13α-methyl-17ß-(1-propinyl)-9-gonen-5α,17α-diol vom Schmelzpunkt 167 - 170 °C.
  

By acidic hydrolysis of 1.0 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -17β- [3- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] - 13α-methyl-17ß- (1-propynyl) -9-gonen-5α, 17α-diol analogously to Example 1, 560 mg of the title compound amorphous are obtained after chromatography of the crude product on silica gel with hexane / acetone.

The raw material is manufactured in the following way:

• a) Under the conditions of Example 3a), a solution of 3.5 g of that obtained in Example 4c) is irradiated. Ketons in 525 ml of dioxane. Chromatography of the crude product on Al ₂ O ₃ with hexane / ethyl acetate and crystallization of the main fraction from diisopropyl ether gives 1.97 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [3- (5,5-dimethyl -1,3-dioxan-2-yl) phenyl] -5α-hydroxy-13α-methyl-9-gonen-17-one with a melting point of 209-211 ° C.
  
• b) By reaction of the product obtained under a) (1.8 g) with methyl acetylene under the conditions of Example 2a), after chrocatography and crystallization from ethyl acetate / diisopropyl ether, 1.12 g of 3,3- (2,2-dimethyl - trimethylene dioxy) -11ß- [3- (3,5-dimethyl-1,3-dioxan-2-yl) phenyl] -13α-methyl-17ß- (1-propynyl) -9-gonen-5α, 17α- diol with melting point 167-170 ° C.
  

Example 6 11β- (4-acetylphenyl) -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one

Die Herstellung des Aussangsmaterials erfolgt auf folgendem Wege:

• a) Aus 50,0 g 4-Bromacetophenon, 75 g 2,2-Dimethylpropan-1,3-diol, 37,6 ml Orthoameisensäuretrimethylester und 30 mg p-Toluolsulfonsäure in 500 ml Dichlormethan erhält man unter den Bedingungen der Beispiele 1 a) und 4 a) nach Chromatographie des Rohprodukts an Al₂O₃ mit Hexan/Ethylacetat 73 g des Ketals als farbloses Öl.
• b) Aus 1⁴,1 g 3,3-(2,2-Dimethyl-trimethylendioxy)-5α,10α-epoxy-9(11)-estren-17ß-ol, 4,12 g Magnesium, 55,92 g des unter a) erhaltenen Bromketals, 0,05 ml Iodmethan und 874 mg CuCl in insgesamt 390 ml THF erhält man unter den Bedingungen des Beispiels 1 b) nach Chromatographie 14,6 g Addukt als farbloses Öl.
• c) Durch Oppenauer-Oxidation analog Beispiel 1 c) erhält man aus 12,8 g des unter b) erhaltenen Grignardprodukts nach Kristallisation des Rohprodukts aus Ethylacetat/Diisopropylether 11,5 g des 17-Ketons vom Schmelzpunkt 211 - 215 °C.

By reacting 2.36 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- {1,1- (2,2-dimethyl-trimethylene-dioxy) -ethyl] phenyl] -5α-hydroxy -9-estren-17-one with methyl acetylene under the conditions of Example 2a) and subsequent acetic acid hydrolysis of the crude product under the conditions of Example 1 yield 1.14 g of the title compound of melting point 151-154 ° C. (from hexane / acetone ).

The source material is produced in the following way:

• a) From 50.0 g of 4-bromoacetophenone, 75 g of 2,2-dimethylpropane-1,3-diol, 37.6 ml of trimethyl orthoformate and 30 mg of p-toluenesulfonic acid in 500 ml of dichloromethane are obtained under the conditions of Examples 1 a) and 4 a) after chromatography of the crude product on Al ₂ O ₃ with hexane / ethyl acetate, 73 g of the ketal as a colorless oil.
• b) From 1 ⁴ , 1 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -5α, 10α-epoxy-9 (11) -estren-17ß-ol, 4.12 g of magnesium, 55.92 g of the with a) bromoketal obtained, 0.05 ml iodomethane and 874 mg CuCl in a total of 390 ml THF, 14.6 g adduct is obtained as a colorless oil after chromatography under the conditions of Example 1 b).
• c) By Oppenauer oxidation analogously to Example 1 c) 11.5 g of the 17-ketone of melting point 211-215 ° C. is obtained from 12.8 g of the Grignard product obtained under b) after crystallization of the crude product from ethyl acetate / diisopropyl ether.

Example 7 11β- (4-acetylphenyl) -17α-hydroxy-13α-methyl-17β- (1-propynyl) -4,9-gonadien-3-one

Irradiation of 4.0 g of the ketone obtained in Example 6 c) under the conditions of Example 3 a), reaction of the product thus obtained with methyl acetylene under the conditions of Example 2 a) and subsequent splitting off of acetic acid analogously to 1 gives 1.09 g 11β- (4-acetylphenyl) -17α-hyrdroxy-13α-methyl-17β- (1-propynyl) -4,9-gonadien-3-one, amorphous.

Example 8 17β-Hydroxy-11β- [4- (3-oxo-1 (E) propenyl) phenyl] -17α- (1-propynyl) -4,9-estradien-3-one

A solution of 750 mg of 17β-hydroxy-11β- [4- (3-hydroxy-1- (E) propenyl) phenyl] -17α- (1-propynyl) -4,9-estradien-3-one in 20 ml of dichloromethane is stirred for 15 minutes after adding 4.0 g of manganese dioxide at room temperature. The mixture is then filtered through Celite and the filtrate is concentrated. 620 mg of 17-hydroxy-11β- [4- (3-oxo-1 (E) propenyl) phenyl] -17α- (1-propynyl) -4,9-estradien-3-one, amorphous, are obtained.

• a) Zu einer Lösung von 20,0 g 4-Brombenzaldehyd in 300 ml abs. THF tropft man bei -10 °C 81 ml einer 1,6-molaren Lösung von Vinylmagnesiumbromid in THF. Nach Zugabe rührt man 60 Minuten bei 0 °C, gießt in Eiswasser und extrahiert mit Ethylacetat. Nach Chromatographie an Al₂O₃ mit Hexan/Ethylacetat erhält man 18,6 g 4-(1-Hydroxy-2-propenyl)-brombenzol als farbloses Öl.
• b) Das unter a) erhaltene Produkt (18,6 g) wird in 100 ml THF gelöst und nach Zugabe von 25 ml Dihydropyran und 0,02 ml POCl₃ 3 Stunden bei Raum emperatur gerührt. Anschließend gießt man in gesättigte NaHCO₃-Lösung und extrahiert mit Diethylether. Chromatographie des Rohprodukts an Al₂O₃ mit Hexan/Ethylacetat liefert 19,2 g 4-[3-(Tetrahydropyran-2-yloxy)-1(E)-propenyl]-brombenzol als farbloses Öl.
• c) Aus 920 mg Magnesium in 15 ml abs. THF, 0,05 ml Iodmethan und 13,0 g des unter b) erhaltenen Bromids in 50 ml THF wird ein Grignard-Reagenz hergestellt und nach Zusatz von 195 mg CuCl mit 5,0 g 3,3-(2,2-Dimethyl-trimethylendioxy)-5α,10α-epoxy-9(11)-estren-17β-ol in 50 ml THF unter den Bedingungen des Beispiels 1 b) umgesetzt; die Reaktionszeit beträgt jedoch 24 Stunden. Nach chromatographischer Reinigung des Rohprodukts erhält man 4,5 g des Addukts als gelbliches Öl.
• d) Durch Oppenauer-Oxidation des unter c) erhaltenen Addukts analog Beispiel 1 c) erhält man aus 3,3 g Edukt nach Chromatographie an Al₂O₃ mit Hexan/Ethylacetat 2,94 g des 17-Ketons als Öl.
• e) Umsetzung des unter d) erhaltenen Ketons (2,9 g) mit Methylacetylen unter den Bedingungen des Beispiels 2 a) und saure Spaltung des so erhaltenen Rohprodukts unter den Bedingungen des Beispiels 1 ergibt 960 mg 17β-Hydroxy-11β-[4-(3-hydroxy-1(E)-propenyl)-phenyl]-17α-(1-propinyl)-4,9-estradien-3-on als festen Schaum.

The raw material is manufactured in the following way:

• a) To a solution of 20.0 g 4-bromobenzaldehyde in 300 ml abs. THF is added dropwise at -10 ° C 81 ml of a 1.6 molar solution of vinyl magnesium bromide in THF. After the addition, the mixture is stirred at 0 ° C. for 60 minutes, poured into ice water and extracted with ethyl acetate. After chromatography on Al ₂ O ₃ with hexane / ethyl acetate, 18.6 g of 4- (1-hydroxy-2-propenyl) bromobenzene are obtained as a colorless oil.
• b) The product obtained under a) (18.6 g) is dissolved in 100 ml THF and stirred emperature after addition of 25 ml of dihydropyran and 0.02 ml of POCl ₃ 3 hours at room. Then poured into saturated NaHCO ₃ solution and extracted with diethyl ether. Chromatography of the crude product on Al ₂ O ₃ with hexane / ethyl acetate gives 19.2 g of 4- [3- (tetrahydropyran-2-yloxy) -1 (E) -propenyl] bromobenzene as a colorless oil.
• c) From 920 mg magnesium in 15 ml abs. THF, 0.05 ml iodomethane and 13.0 g of the bromide obtained under b) in 50 ml THF, a Grignard reagent is prepared and after the addition of 195 mg CuCl with 5.0 g 3,3- (2,2-dimethyl -trimethylenedioxy) -5α, 10α-epoxy-9 (11) -estren-17β-ol in 50 ml THF under the conditions of Example 1 b) implemented; however, the response time is 24 hours. After the crude product has been purified by chromatography, 4.5 g of the adduct are obtained as a yellowish oil.
• d) Oppenauer oxidation of the adduct obtained under c) analogously to Example 1 c) gives 2.94 g of the 17-ketone as an oil from 3.3 g of educt after chromatography on Al ₂ O ₃ with hexane / ethyl acetate.
• e) Reaction of the ketone (2.9 g) obtained under d) with methyl acetylene under the conditions of Example 2a) and acidic cleavage of the crude product thus obtained under the conditions of Example 1 gives 960 mg of 17β-hydroxy-11β- [4- (3-hydroxy-1 (E) propenyl) phenyl] -17α- (1-propynyl) -4,9-estradien-3-one as a solid foam.

Example 9

• a) 2,17 g 11β-[4-(anti-Hydroxyiminomethyl)-phenyl]-17β-hydroxy-17α-(1-propinyl)-4,9-estradien-3-on-anti-oxim vom Schmelzpunkt 242 - 244 °C.
• b) 880 mg 11β-[4-(anti-Hydroxyiminomethyl)-phenyl]-17β-hydroxy-17α-(1-propinyl)-4,9-estradien-3-on-syn-oxim vom Schmelzpunkt 243 - 251 °C.

To a solution of 4.07 g (11β- (4-formylphenyl) -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one (see Example 2) in 60 ml of pyridine is added 3.65 g of hydroxylamine hydrochloride in portions with ice-water cooling After stirring, the mixture is stirred at +5 C for 30 minutes, poured into a mixture of ice-water / 0.5N hydrochloric acid and extracted with dichloromethane by fractional crystallization of the crude product (4.53 g) from ethyl acetate one obtains:

• a) 2.17 g of 11β- [4- (anti-hydroxyiminomethyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one-anti-oxime, melting point 242-244 ° C.
• b) 880 mg of 11β- [4- (anti-hydroxyiminomethyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one-syn-oxime with a melting point of 243-251 ° C .

Example 10 11β- (4-formylphenyl) -17β-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -4,9-estradien-3-one

Reaction of 5.71 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -17α- [3 - (tetrahydropyran-2-yloxy) -1 (Z) -propenyl] -9-estrene-5α, 17β-diol with 70 ml of 70% acetic acid under the conditions of Example 1 gives 2.3 g of 11β- (after chromatographic purification 4-formylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -4,9-estradien-3-one as a solid foam.

Die Herstellung des Ausgangsmaterials erfolgt auf folgendes Wege:

• a) Aus 6,35 g 3-(Tetrahydropyran-2-yloxy)-1-propin in 115 ml abs. THF und 31,6 ml einer 15 %igen Lösung von n-Butyllithium in Hexan stellt man bei 0 °C die lithiumorganische Verbindung her und tropft dazu bei 0 bis +5 °C eine Lösung von 5,1 g des unter Beispiel 1 c) erhaltenen Ketons in 70 ml abs. THF. Man rührt anschließend 3 Stunden bei Raumtemperatur, gießt danach in Eiswasser und extrahiert mit Ethylacetat. Das Rohprodukt wird an neutralem Aluminiumoxid mit Hexan/Ethylacetat chromatographiert. Als ölige Hauptfraktion erhält man 7,2 g 3,3-(2,2-Dimethyl- trimethylendioxy)-11β[4-(5,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-17α-[3-(tetrahydropyran-2-yloxy)-1-propinyl]-9- estren,-5α,17β-diol.
• b) Eine Lösung von 5,7 g des unter a) erhaltenen Produkts in 75 ml THF wird nach Zusatz von 5 ml Pyridin und 560 mg Palladium/Bariumsulfat (10 % Pd) bei Raumtemperatur und Normaldruck hydriert. Nach Stillstand der Wasserstoffaufnahme filtriert man vom Katalysator ab und engt das Filtrat ein. Man erhält 5,71 g 3,3-(2,2-Dimethyl- triamethylendioxy)-11β-[4-(5,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-17α-[3-(tetrahydropyran-2-yloxy)-1(Z)-propenyl]-9-estren-5α,17β-diol als Öl.

The raw material is manufactured in the following ways:

• a) From 6.35 g of 3- (tetrahydropyran-2-yloxy) -1-propyne in 115 ml of abs. THF and 31.6 ml of a 15% solution of n-butyllithium in hexane, the organolithium compound is prepared at 0 ° C and a solution of 5.1 g of the solution from Example 1 c) is added dropwise at 0 to +5 ° C) obtained ketones in 70 ml abs. THF. The mixture is then stirred for 3 hours at room temperature, then poured into ice water and extracted with ethyl acetate. The crude product is chromatographed on neutral aluminum oxide with hexane / ethyl acetate. As main oily fraction gives 7.2 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β [4- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl] -17α- [ 3- (tetrahydropyran-2-yloxy) -1-propynyl] -9- estrene, -5α, 17β-diol.
• b) A solution of 5.7 g of the product obtained under a) in 75 ml of THF is hydrogenated after adding 5 ml of pyridine and 560 mg of palladium / barium sulfate (10% Pd) at room temperature and normal pressure. After the hydrogen uptake has ceased, the catalyst is filtered off and the filtrate is concentrated. 5.71 g of 3,3- (2,2-dimethyltriamethylenedioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -17α- [3 are obtained - (tetrahydropyran-2-yloxy) -1 (Z) -propenyl] -9-estrene-5α, 17β-diol as an oil.

Example 11 11β- (4-formylphenyl) -17β-hydroxy-13α-methyl-17α- (1-propynyl) -4,9-gonadien-3-one

Die Herstellung des Ausgangsmaterials erfolgt auf folgendem Wege:

• Bei der unter 3 b) beschriebenen Additionsreaktion mit Methylacetylen erhält man nach der Chromatographie als unpolares Nebenprodukt 480 mg 3,3-(2,2-Dimethyl-trimethylen- dioxy)-11β-[4-(5,5-dimethyl-1,3-dioxan-2-yl)-phenyl]-13α-methyl-17α-(1-propinyl)-9-gonen-5α,17β-diol als gelbliches Öl.

420 mg of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] - are added under the conditions of Example 1. 13α-methyl-17α- (1-propynyl) -9-gonen-5α, 17β-diol with 6.5 ml of 70% acetic acid at 60 ° C. After chromatography of the crude product on silica gel with hexane / ethyl acetate, 180 mg of the title compound are obtained as a yellowish foam.

The raw material is manufactured in the following way:

• In the addition reaction with methyl acetylene described under 3 b), 480 mg of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- (5,5-dimethyl-1, 3-dioxan-2-yl) phenyl] -13α-methyl-17α- (1-propynyl) -9-gonen-5α, 17β-diol as a yellowish oil.

Example 12 11β- (4-acetylphenyl) -17β-hydroxy-9α, 10α-methylene-17α- (1-propynyl) -4-estren-3-one

By reaction of 6.2 g .3,3- (2,2-dimethyl-trimethylene-dioxy) -11ß- [4- {1,1- (2,2-dimethyl-trimethylene-dioxy) -ethyl} -phenyl] -9α, 10α-methylene-17α- (1-prop-ynyl) -estran-5α, 17β-diol with 60 ml of 70% aqueous acetic acid under the conditions of Example 1) gives 3.14 g after crystallization of the crude product from ethyl acetate / diisopropyl ether the title compound of melting point 233-235 ° C, [α] ²⁵ _D = + 36.4 ° (CHC1 ₃ , c = 0.505). :

Production of the starting material:

• a) To a suspension of 96 g zinc dust in 360 ml abs. THF and 1.73 g of copper (II) acetate are slowly added dropwise at room temperature to 9.6 ml of glacial acetic acid. The mixture is subsequently stirred at 25 ° C. for 15 minutes and then 3.36 ml of triethylamine are added dropwise to the suspension. Then a solution of 21.0 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- {1,1- (2,2-dimethyl-trimethylene-dioxy) -ethyl} -phenyl] -9 -estren-5α, 17β-diol in 190 ml abs THF added dropwise within 15 minutes. Subsequently, 67.2 ml of dibromomethane are added dropwise so that the reaction solution warms to a low boil. After the addition (about 45 minutes), the mixture is heated under gentle reflux for a further 2 hours and then stirred for a further 12 hours at room temperature. For working up, about 300 ml of saturated NH ₄ Cl solution are added dropwise to the reaction suspension with ice-water cooling, diluted with methylene chloride, filtered through Celite and the filtrate is washed several times with aqueous ammonia. The crude product is chromatographed on Al203 (Merck, neutral, stage III) with hexane / ethyl acetate. After crystallization of the main fraction from ethyl acetate, 13.4 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- {1,1- (2,2-dimethyl-trimethylene-dioxy) -ethyl} -phenyl are obtained ] -9α-10α-methylene-estran-5a, 17ß-diol melting point 170-174 ° C. [α] ²⁵ _D = + 55.2 ° (CH ₂ Cl ₂ , c = 0.510).
• b) Oppenauer oxidation of 5.9 g of the product obtained under a) according to the conditions of Example 1c) gives 5.2 g of the 17- after chromatography on Al ₂ 0 ₃ with hexane / ethyl acetate and crystallization from hexane / diisopropyl ether. Ketones with a melting point of 206-208 ° C.
  
• c) By reacting 5.3 g of the ketone obtained under b) with methyl acetylene under the conditions of Example 2a), after crystallizing the crude product from ethyl acetate / diisopropyl ether, 4.85 g of the starting product required for the final stage, melting point 146-149 °, are obtained C.
  

Example 13 11β- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-l (Z) -propenyl) -9α, 10α-methylene-4-estren-3-one

Reaction of 5.9 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- {1,1- (2,2-dimethyl-trimethylene-dioxy) -ethyl} -phenyl] -9α, 10α- methylene-17α- [3- (tetrahydropyran-2-yloxy) -1 (Z) -propenyl] -estran-5α, 17β-diol with 58 ml of 70% aqueous acetic acid analogously to Example 1, after crystallization of the crude product from acetone 2, 16 g of the title compound of melting point 145-149 ° C.

Production of the starting material:

The ketone obtained in Example 12b) (7.5 g) is reacted with propargyl alcohol tetrahydropyranyl ether under the conditions of Example 10a) and the adduct thus obtained is hydrogenated without further purification under the conditions of Example 10b). The starting material mentioned above is obtained as a colorless oil (5.9 g).

Example 14 17β-hydroxy-17α- (1-propynyl) -11β- (4-propionylphenyl) -4,9-estradien-3-one

By treating 11.0 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4 {1,1- (2,2-dimethyl-trimethylene-dioxy) -propyl} -phenyl] -17α- (1-propynyl ) -9-estren-5α, 17β-diol with 49 ml 70% aqueous acetic acid under the conditions of example 1) is obtained after crystallization of the crude product from hexane / acetone 6.2 g of the title compound of melting point 133-136 ⁰ C. .

• a) Aus 66,7 g 4-Brompropiophenon erhält man durch'Ketalisierung mit 100 g 2,2-Dimethyl-propan-1,3-diol nach Chromatographie des Rohprodukts an Al₂0₃ 79,7 g des Ketals als farbloses Öl.
• b) Aus 5,39 g Magnesium, 79,7 g des unter a) erhaltenen Ketals, 20,4 g 3,3-(2,2-Dimethyl-trimethylendioxy)-5α,10α-epoxy-9(11)-estren-17β-ol und 1,24 g CuCl in insgesamt 540 ml abs. THF erhält man unter den Bedingungen des Beispiels 1b) nach Chromatographie 28,7 g des Addukts als gelbliches Öl.
• c) Durch Oppenauer-Oxidation des unter b) erhaltenen Produkts (28,7 g) analog Beispiel 1c) erhält man nach Chromatographie des Rohprodukts 27,5 g des 17-Ketons als festen Schaum.
• d) Umsetzung des unter c) erhaltenen Ketons (10,9 g) mit Methylacetylen unter den Bedingungen des Beispiels 2) ergibt 11,0 g des für die Endstufe benötigten Ausgangsmaterials als farbloses Öl.

Production of the starting material:

• a) From 66.7 g of 4-bromopropiophenone is obtained by ketalization with 100 g of 2,2-dimethyl-propane-1,3-diol after chromatography of the crude product on Al ₂ 0 ₃ 79.7 g of the ketal as a colorless oil.
• b) From 5.39 g of magnesium, 79.7 g of the ketal obtained under a), 20.4 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -5α, 10α-epoxy-9 (11) -estrene -17β-ol and 1.24 g CuCl in a total of 540 ml abs. THF is obtained under the conditions of Example 1b) after chromatography, 28.7 g of the adduct as a yellowish oil.
• c) Oppenauer oxidation of the product obtained under b) (28.7 g) analogously to Example 1c) gives, after chromatography of the crude product, 27.5 g of the 17-ketone as a solid foam.
• d) Reaction of the ketone (10.9 g) obtained under c) with methyl acetylene under the conditions of Example 2) gives 11.0 g of the starting material required for the final stage as a colorless oil.

Example 15 17α-ethynyl-17β-hydroxy-11β- (4-propionylphenyl) -4,9-estradien-3-one

Reaction of 5.9 g of 17α-ethynyl-3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- {1,1- (2,2-dimethyl-trimethylene-dioxy) -propyl} -phenyl } -9-estren-5α, 17β-diol with 25 ml 70% acetic acid under the conditions of Example 1 after crystallization of the crude product from ethyl acetate / diisopropyl ether 1.99 g of the title compound of melting point 114-11 ° C,

Production of the starting material:

The ketone obtained in Example 14c) (5.8 g) is reacted under the conditions of Example 2, but using acetylene instead of propyne. 5.9 g of the ethynylation product are obtained as a colorless oil which is used without further purification for the acetic acid cleavage described above.

Example 16 1 7α-bromoethynyl-17β-hydroxy-11β- (4-propionylphenyl) -4,9-estradien-3-one

A suspension of 1.0 g of 17α-ethynyl-17β-hydroxy-11β- (4-propionylphenyl) -4,9-estradien-3-one, 60 mg of silver nitrate and 700 mg of N-bromosuccinimide in 40 ml of acetone and 6 ml of water is stirred at 25 ° C for 40 minutes. Then poured into NH ₃ solution and extracted with ethyl acetate. Crystallization of the crude product from ethyl acetate gives 720 mg of the title compound from the decomposition point 132 ° C.

Example 17 11β- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl-4,9-estradien-3-one

• a) From 9.74 g of propargyl alcohol tetrahydropyranyl ether, 56.4 ml of a 15% solution of n-butyllithium in hexane and 10.01 g of 3,3- (2,2-dimethyl-trimethylene-dioxy) -11β- [4- {1,1- (2,2-dimethyl-trimethyl-endioxy) -ethy} -phenyl] -5α-hydroxy-9-estren-17-one (preparation see Example 6c) is obtained by the method of Example 10a) Chromatography of the crude product on Al ₂ 0 ₃ with hexane / ethyl acetate 11.66 g of the adduct as an oily mixture of the diastereomeric THP ethers.
• b) Partial hydrogenation of 8.66 g of the product obtained under a) by the process of Example 10b) and subsequent acetic acid cleavage of the crude product analogously to Example 1) gives 2.55 g of 11β- (4 -Acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl-4,9-estradien3-one with melting point 116-118 ° C.
  

Example 18 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxypropyl) -4,9-estredien-3-one

A solution of 3.6 g of the product obtained under 17a) in 30 ml of ethanol is hydrogenated after the addition of 320 mg of palladium-on-carbon (10%) at room temperature and normal pressure to a standstill. After filtering off the catalyst, the mixture is concentrated, the oily crude product (3.6 g) is taken up in 20 ml of 70% acetic acid and the mixture is stirred at 60 ° C for 45 minutes. After working up analogously to Example 1 and chromatography on silica gel with hexane / ethyl acetate, 1.6 g of 11β- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxypropyl) -4,9-estradien-3-one is obtained as a solid Foam.

Example 19 3- [11ß- (4-Acetylphenyl) -17ß-hydroxy-3-oxo-4,9-estradien-17α-yl] propionic acid lactone

A solution of 1.51 of the product obtained in Example 18 in 63 ml of acetone is added dropwise with 2.1 ml of Jones reagent while cooling with ice water. The mixture is then stirred for 15 minutes at room temperature, the reaction solution is poured into water, neutralized by adding aqueous ammonia solution and extracted with dichloromethane. After crystallization of the crude product from hexane / ethyl acetate, 1.06 g of 3- [11β- (4-acetylphenyl) -17ß-hydroxy-3-oxo-4,9-estradien-17α-yl] propionic acid lactone, melting point 243-245, is obtained ° C,

Example 20 11β- (4-acetylphenyl) -15ß, 17ß-dihydroxy-17α- (1-propynyl) -4,9-estradien-3-one

500 ml of a sterile nutrient solution containing 1% glucose, 0.1% yeast extract, 0.1% beef extract, 0.2% tryptose, 1.5% agar with a pH of 7.2 are mixed with a 10 day old Inoculated slant agar culture from Streptomyces platensis (NRRL 2364) and shaken at 30 ° C for 60 hours. 300 ml of this preculture are transferred to a 10 1 fermenter which contains 5 1 sterile medium of the composition given above. With stirring at 220 rpm. and aeration with 5 l air / min the culture is developed at 29 ° C. After 12 hours, 1.0 g of 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) -4,9-estradier-3-one is added in 60 ml of dimethylformamide after sterile filtration. The substrate concentration is 200 mg / l. The reaction is checked by thin layer chromatography. The fermentation is ended after 36 hours of contact. The culture broth is extracted with methyl isobutyl ketone and the extract is concentrated in vacuo at 30-40 ° C. The residue thus obtained becomes Ent Removal of the anti-foaming agent (silicone SH) washed with hexane. It is then chromatographed on silica gel with hexane / ethyl acetate. Crystallization of the main fraction from ethyl acetate / diisopropyl ether gives 400 mg (38.4% of theory) of the title compound of melting point 152-154'C.

Example 21 11β- (4-acetylphenyl) -16α, 17β-dihydroxy-17α- (1-propynyl) -4,9-estradien-3-one

Under the conditions of Example 20, 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one (1.0 g) is used for fermentation with Streptomyces toyocaensis (DSM 40030 ) a. The fermentation time is 95 hours and the contact time is 81 hours. After purification by column chromatography and crystallization from ethyl acetate / hexane, 370 mg of the title compound of melting point 225-229 ° C. are obtained.

Example 22 11β- (4-acetylphenyl) -6a, 17ß-dihydroxy-17α- (1-propynyl) -4,9-estradien-3-one

Under the conditions of Example 20, 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one (1.0 g) is used for fermentation with Nigrospora sphaerica (CBS 98469 ) used. However, it is a medium of the following composition using: 3% glucose, 1% corn steep, _{0, 2%} NaNO _{3, 0, 1%} KH ₂ PO _{4 '0, 2%} K ₂ HPO _4, 0.05% MgSO _4, 0.002 % FeS0 ₄ , 0.05% KC1 of pH 6.0. The fermentation time is 112 hours, the contact time 100 hours. After chromatographic purification, 235 mg of the title compound of melting point 148-152 ° C. (from ethyl acetate) are obtained.

Example 23 11β- (4-acetylphenyl) -7α, 17ß-dihydroxy-17α- (1-propynyl) -4,9-estradien-3-one

Fermentation of 1.0 g of 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one under the conditions of Example 20 and using the medium in Example 22 with After chromatographic purification, Neurospora crassa (ATCC 9278) gives 196 mg of the title compound with a melting point of 156-159 ° C. (from hexane / ethyl acetate). The fermentation time in this case is 123 hours, the contact time 112 hours.

Example 24 11β- (4-acetylphenyl) -6ß-chloro-17ß-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one

A solution of 140 mg of the 11β- (4-acetylphenyl) -6α, 17β-dihydroxy-17α- (1-propynyl) -4,9-estradien-3-one obtained in Example 22 in 3 ml dichloromethane, 0.02 ml Pyridine and 0.4 ml carbon tetrachloride are stirred for 2 hours at + 5 ° C after the addition of 840 mg triphenylphosphine. Then poured into NH ₄ Cl solution and extracted with dichloromethane. The crude product is chromatographed on silica gel with hexane / ethyl acetate. 116 mg of the title compound are obtained as an amorphous powder with a pseudo melting point of 140-144 ° C.

Example 25 11β- (4-acetylphenyl) -17ß-hydroxy-6ß-methyl-17α- (1-propynyl) -4,9-estradien-3-one

570 mg of copper (I) iodide are added in portions to 5.2 ml of a 5% strength solution of methyl lithium in diethyl ether at 0 ° C. After the copper salt has completely dissolved, a solution of 640 mg of 11β- (4-acetylphenyl) -17β-hydroxy-17α- (1-propynyl) -6α-tosyloxy-4,9-estradien-3-one is added dropwise at -20 ° C. in 5 ml THF and 5 ml diethyl ether and then stirred for 60 minutes at -20 to -10 ° C. For working up, it is poured into aqueous ammonia solution and extracted with ethyl acetate. After chromatography on silica gel and crystallization of the main fraction from diisopropyl ether, 360 mg of the title compound of melting point 129-131 ° C. are obtained.

• Eine Lösung von 560 mg 11ß-(4-Acetylphenyl)-6α,17ß-dihydroxy-17α-(1-propinyl)-4,9-estradien-3-on in 4,5 ml Pyrridin wird unter Eiswasserkühlung mit 960 mg p-Toluolsulfonsäurechlorid versetzt und 5 Stunden bei +5°C gerührt. Anschließend gießt man in 30 ml 0,5 n wäßrige Salzsäure und extrahiert mehrmals mit Ethylacetat. Die Extrakte werden mit Wasser und gesättigter NaHCO₃-Lösung gewaschen, über Na₂SO₄ getrocknet und eingeengt. Man erhält ein gelbliches Öl (640 mg), das ohne weitere Reinigung in die obige Reaktion eingesetzt wird.

Production of the starting material:

• A solution of 560 mg of 11ß- (4-acetylphenyl) -6α, 17ß-dihydroxy-17α- (1-propynyl) -4,9-estradien-3-one in 4.5 ml of pyrridine is cooled with 960 mg of p- Toluene sulfonic acid chloride was added and the mixture was stirred at + 5 ° C. for 5 hours. Then poured into 30 ml of 0.5 N aqueous hydrochloric acid and extracted several times with ethyl acetate. The extracts are washed with water and saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated. A yellowish oil (640 mg) is obtained, which is used in the above reaction without further purification.

Claims (6)

For the contracting states BE, CH, DE, FR, GB, IT, LU, NL, SE. 1. 13-alkyl-11β-phenyl-gonanes of the general formula I

wherein A and B together for an oxygen atom, a CH ₂ group or a second bond between, the carbon atoms 9 and 10, X represents an oxygen atom or the hydroxyimino group N-OH, R ₁ for a straight-chain or branched, saturated or. unsaturated hydrocarbon residue with up to 8 carbon atoms, which is the grouping

with X in the meaning given above, R ₂ for an α- or ß-methyl or ethyl radical, in the case of an α-methyl or ethyl radical R ₃ / R ₄ -CR ₅ / -C≡CY -C≡CY / -OR ₅ -CR ₅ /

/ -CR ₅ -CH ₃ /

/ -CH ₃ -H /

/ -H -OR ₅ / - (CH ₂ ) _m -CH ₂ -R ₇ - (CH ₂ ) _m CH ₂ -R ₇ / -OR ₅ -OR ₅ / -CH = CH- (CH ₂ ) _k -CH ₂ -R ₇ -CH = CH- (CH ₂ ) _k -CH ₂ -R ₇ / -OR ₅ -OR ₈ / -H -H / -OR ₈

and in the case of a β-methyl or ethyl radical R ₂ R ₃ / R ₄ -OR ₅ / -C≡CY -OR ₅ /

/ -OR ₅

/ -CH ₃

/ -H -OR ₅ / - (CH ₂ ) _m -CH ₂ -R ₇ -OR ₅ / -CH = CH- (CH ₂ ) _k -CH ₂ -R ₇ -OR ₈ / -H

with R ₅ in the meaning of a hydrogen atom or acyl radical having 1 to 4 carbon atoms, Y in the meaning of a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group each having 1 to 4 carbon atoms in the alkyl or acyl radical, R _{6 has} the meaning of a hydrogen atom, a hydroxyl group, an alkyl, O-alkyl or O-acyl group each having 1 to 4 carbon atoms, m has the meaning 0, 1, 2 or 3, R _{7 has} the meaning of a hydroxyl or cyanide radical, an O-alkyl or O-acyl group each having 1 to 4 carbon atoms and k has the meaning 0, 1 or 2, R _{8 has} the meaning of a hydrogen atom, an alkyl or acyl group each having 1 to 10 carbon atoms, R _{9 '} R _10' R ₁₁ and R ₁₂ each represent a hydrogen atom, a hydroxyl, alkyl, alkoxy or acyloxy group each having 1 to 4 carbon atoms or a halogen atom, and the substituent of the 11β-phenyl radical is in the 3- or 4-position. 2. 17α-ethynyl-11ß- (4-formylphenyl) -17ß-hydroxy-4,9-estradien-3-one, 11ß- (4-formylphenyl) -17ß-hydroxy-17α- (1-propynyl) -4, 9-estradien-3-one, 11β- (4-formylphenyl) -17α-hydroxy-13α-methyl-17ß- (1-propynyl) -4,9-gonadien-3-one, 11β- (3-formylphenyl) -17ß-hydroxy-17α- (1-propynyl) -4,9-estradiene 3-one, 11β- (3-formylphenyl) -17α-hydroxy-13α-methyl-17ß- (1-propynyl) -4,9-gonadien-3-one, '. 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one, 11β- (4-acetylphenyl) -17α-hydroxy-13α-methyl-17ß- (1-propynyl) -4,9-gonadien-3-one, 11β- (4-formylphenyl) -17ß-hydroxy-17α- (3-hydroxypropyl) -4,9- estradien-3-one, 11β- (4-formylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -4,9-estradien-3-one, 3- [11β- (4-formylphenyl) -17B-hydroxy-3-oxo-4,9-estradien-17α-yl] propionic acid lactone, 17β-hydroxy-11ß- [4- (3-oxo-1 (E) -propenyl) phenyl] -17α- (1-propynyl) -4,9-estradien-3-one, 11β- [4- (anti-hydroxyiminomethyl) phenyl] -17ß-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one anti-oxime. 11β- [4- (anti-hydroxyiminomethyl) phenyl] -17ß-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one-syn-oxime, 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -4,9-estradien-3-one, 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxypropyl) -13α-methyl-4,9-gonadien-3-one, 11β- (4-acetylphenyl) -17ß-hydroxy-17α-methoxymethyl-4,9-estradien-3-one, 11β- (4-formylphenyl) -17α-hydroxy-13α-methyl-18,19-dinor-4,9-pregnadier-3,20-dione, 17α-acetoxy-11ß- (4-formylphenyl) -13α-methyl-18,19-dinor-4,9-pregnadien-3,20-dione, 11β- (4-formylphenyl) -17ß-hydroxy-13α-methyl-17α- (1-propynyl) - ₄ , 9-gonadien-3-one _r 11β- (4-acetylphenyl) -17ß-hydroxy-9α, 10α-methylene-17α (1-propynyl) -4-estren-3-one, 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -9α, 10α-methylene-4-estren-3-one, 17β-hydroxy-17α- (1-propynyl) -11ß- (4-propionylphenyl) -4,9-estradien-3-one, 17α-ethynyl-17ß-hydroxy-11ß- (4-propionylphenyl) -4,9-estradien-3-one, 17α-bromoethynyl-17ß-hydroxy-11ß- (4-propionylphenyl) -4,9-estradien-3-one, 11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxypropyl) -4,9- estradien-3-one, 3- [11ß- (4-acetylphenyl) -17ß-hydroxy-3-oxo-4,9-estradien-17α-yl] -4-propionic acid lactone, 11ß- (4-acetylphenyl) -15ß, 17ß-dihydroxy-17α- (1-propinyl) -4,9- estradien-3-one, 11β- (4-acetylphenyl) -16α, 17ß-dihydroxy-17α- (1-propynyl) -4,9- estradien-3-one, 11β- (4-acetylphenyl) -6α-17ß-dihydroxy-17α- (1-propynyl) -4,9-estradien-3-one, 11β- (4, -acetylphenyl) -7α, 17ß-dihydroxy-17α- (1-propynyl) -4,9- estradien-3-one, 11β- (4-acetylphenyl) -6ß-chloro-17ß-hydroxy-17α- (1-propynyl) -4,9- estradien-3-one, 11β- (4-acetylphenyl) -17ß-hydroxy-6ß-methyl-17α- (1-propynyl) -4,9-estradien-3-one, 17β-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -11ß- (4-propionylphenyl) -4,9-estradien-3-one, 16. 11B- (4-acetylphenyl) -17α-bromethinyl-1 / B-hydroxy-4,9-astradien-3-one. 3. Process for the preparation of compounds of general formula I.

wherein A and B together for an oxygen atom, a CH ₂ group or a second bond between the carbon atoms 9 and 10, X for an oxygen atom or the hydroxyimino group N-OH, R ₁ for a straight-chain or branched, saturated or unsaturated hydrocarbon residue with up to 8 carbon atoms, which the grouping

with X in the meaning given above, _R2 for an α or β-methyl or ethyl radical, in the case of an α-methyl or ethyl radical R ₃ / R ₄ -OR ₅ / -C≡CY -C≡CY / _OR ₅ -OR ₅ /

/ -OR ₅ -CH ₃ /

_/ -C ^H 3 -H /

/ - H -OR ₅ / - (CH ₂ ) _m -CH ₂ -R ₇ - (CH ₂ ) _m -CH ₂ -R ₇ / -OR ₅ -OR ₅ / -CH = FH- (CH ₂ ) _k - CH ₂ -R ₇ -CH = CH- (CH ₂ ) _k -CH ₂ -R ₇ / -OR ₅ -CR ₈ / -H -H / -OR ₈

and in the case of a β-methyl or ethyl radical R ₂ R ₃ / R ₄ -OR ₅ / -C≡CY -OR ₅ /

_/ -OR ₅

/ -CH ₃

/ -H -OR ₅ / - (CH ₂ ) _m -CH ₂ -R ₇ -OR ₅ / -CH = CH- (CH ₂ ) _k -CH ₂ -R ₇ -OR ₈ / -H

with R ₅ in the meaning of a hydrogen atom or acyl radical with 1 to 4 carbon atoms, Y in the meaning of a. Hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group each having 1 to 4 carbon atoms in the alkyl or acyl radical, R _{6 has} the meaning of a hydrogen atom, a hydroxyl group, an alkyl, O-alkyl or O-acyl group each having 1 to 4 carbon atoms, m has the meaning 0, 1, 2 or 3, R _{7 has} the meaning of a hydroxyl or cyanide radical, a 0-alkyl or 0-acyl group each having 1 to 4 carbon atoms and k has the meaning 0, 1 or 2, R _{8 has} the meaning of a hydrogen atom, an alkyl or acyl group each having 1 to 10 carbon atoms, R ₉ , R ₁₀ , R ₁₁ and R ₁₂ each represent a hydrogen atom, a hydroxyl, alkyl, alkoxy or acyloxy group each having 1 to 4 carbon atoms or a halogen atom, and the substituent of the 11β-phenyl radical is in the 3- or 4-position, characterized in that a compound of the general formula II

wherein K is a keto group blocked in the form of the ketal, thioketal, oxime or methyloxime, A,. B and R _{2 have} the meaning given above, R ' _{1 has} the same meaning as R, but instead of

- Grouping contains, R ' _{3 has} the same meaning as R ₃ , with any hydroxy groups present being protected and R' _{4 has} the same meaning as R ₄ , with any hydroxy or acyl groups present being protected and K _{1 in} addition to those mentioned above Meanings for K still stands for a hydrogen atom and a protected hydroxy group, the action of a dehydrating agent, which is also capable of releasing the protected function (s), subject to elimination of water with simultaneous formation of the 4 (5) double bond, one contained in K ₁ Hydroxy group oxidizes, if desired the compounds of the general formula I thus obtained with R9, R ₁₀ , R ₁₁ and R12 each having a hydrogen atom by microbiological hydroxylation with microorganisms of the species Steptomyces toyccaensis (DSM 40030) and / or Steptomyces platensis (NRRL 2364) and / or Nigrospora sphaerica (CBS 98469) and / or Neurospora crassa ( _A TCC 9278) tzt and the thus obtained hydroxylated compounds of general formula I, wherein at least one of the substituents R ₉ , R ₁₀ , R ₁₁ and R ₁₂ stand for the hydroxyl group, the remaining substituents for hydrogen, if desired epimerizes at the positions bearing the hydroxyl groups, which If desired, hydroxyl groups are etherified, esterified or substituted by a halogen or alkyl radical, if desired the hydroxyl groups present in R ₃ and R ₄ are esterified or esterified with X in the meaning of an oxygen atom to form the product of the general formula I and then if desired subsequently with hydroxylamine hydrochloride In the presence of tertiary amines at temperatures between -20 ° C and + 40 ° C. 4. Pharmaceutical preparations, characterized by a content of compounds according to claims 1 to 2. 5. Use of compounds according to claims 1 to 2. for the production of medicaments.